Differentiation and tumorigenesis: Understanding the mechanisms of regulation of cellular proliferation, migration and differentiation is basic to understanding development of multicellular organisms. One approach to investigating these cellular regulatory mechanisms is to study the behavior of tumor cells that have become abnormal in regulation of these processes as a result of viral transformation. Through the use of cell hybrids formed between Ad2 and SV40 transformed cells, we are beginning to identify the phenotypic characteristics of the transformed cells (e.f., expression of specific viral antigens and cellular fibronectin, and sensitivity to lysis by immune effector cells) that correlate with their ability to form tumors in syngeneic animals. In addition, we find that Ad2-transformed cells appear to be more active than SV40-transformed cells in production of mitogenic factors. We are also developing the SV40 system to study the genetic basis of tumor metastasis. We have found that tumors induced in hamsters by a mutant of SV40 virus develop more slowly than normal and metastasize more frequently. By studying the properties of these abnormal tumor cells we expect to learn more about how cell proliferation and migration are regulated on the genetic level. Mutagenesis: Chromosomal mutations are the underlying cause of most inherited diseases and many developmental abnormalities. Mutations also appear to play a role in carcinogenesis by a variety of environmental agents. We are using SV40 virus as a probe to investigate the molecular mechanisms by which these agents induce mutations in mammalian cells. Our studies on replication of UV-damaged SV40 DNA have led to a well-defined model of how the mammalian cell replication machinery responds to DNA damage and at what steps in the replication process mutations become irreversibly established. By use of a SV40-derived shuttle vector system we are also beginning to characterize the types of mutations induced by specific agents and to correlate these with the mechanism of mutation induction.